There is an ever increasing number of pharmaceutical drugs being formulated that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges to delivering them in an injectable form such as through parenteral administration. A well-designed formulation must, at a minimum, be capable of presenting a therapeutically effective amount of the poorly soluble drug to the desired absorption site, in an absorbable form. In addition, these compositions tend to be unstable, with sedimentation and/or precipitation occurring in under 24 hours following rehydration or reconstitution.
Taxanes, in particular the two currently available taxane drugs, paclitaxel and docetaxel, are potent antitumor agents. Paclitaxel is very poorly water soluble (less than 10 μg/mL), and as a result, cannot be practically formulated with an aqueous medium for IV administration. Currently, paclitaxel is formulated for IV administration to patients with cancer in a solution with polyoxyethylated castor oil (Polyoxyl 35 or Cremophor®) as the primary solvent/surfactant, with high concentrations of ethanol employed as co-solvent. One of the major difficulties in the administration of paclitaxel is the occurrence of hypersensitivity reactions. These reactions, which include severe skin rashes, hives, flushing, dyspnea, tachycardia and others, may be attributed at least in part to the high concentrations of ethanol and Cremophor used as solvents in the formulation. Docetaxel, an analog of paclitaxel, is semisynthetically produced from 10-deacetyl baccatin III, a noncytotoxic precursor extracted from the needles of Taxus baccata and esterified with a chemically synthesized side chain (Cortes and Pazdur, 1995, J. Clin. Oncol. 13(10):2643-55). Like paclitaxel, docetaxel is very poorly soluble in water. Currently, the most preferred solvent/surfactant used to dissolve docetaxel is polysorbate 80 (Tween 80) (Bissery et al. 1991 Cancer Res. 51(18):4845-52; Tomiak et al. 1992). Like Cremophor, Tween often causes hypersensitivity reactions in patients. Further, Tween 80 cannot be used with PVC delivery apparatus because of its tendency to leach diethylhexyl phthalate, which is highly toxic.
Purification of semi-synthetic paclitaxel and docetaxel is a challenging problem due to the formation of a number of degradation products along the synthetic route. Furthermore, purified taxanes are found to undergo degradation, even under controlled storage conditions. Therefore, it becomes desirable to develop stable forms of these molecules which retain the desirable anti-cancer properties. Previous efforts in obtaining suitable docetaxel have been focusing on processes of preparing trihydrate forms of docetaxel, which were believed to have substantially greater stability than that of the anhydrous product. See, e.g., U.S. Pat. Nos. 6,022,985; 6,838,569.
In order to attain the expected therapeutic effects of poorly water soluble agents such as paclitaxel and docetaxel, it is usually required that a solubilized forth or nanodispersed form of the agent be administered to a patient.
Thus, a number of methods have been developed which are based on the use of: auxiliary solvents; surfactants; soluble forms of the drug, e.g., salts and solvates; chemically modified forms of the drug, e.g., prodrugs; soluble polymer-drug complexes; special drug carriers such as liposomes; and others. Indeed, the use of amphiphilic block copolymer micelles has attracted a great deal of interest as a potentially effective drug carrier which is capable of solubilizing a hydrophobic drug in an aqueous environment.
Each of the above methods is hampered by one or more particular problems. For example, the method based on the use of surfactant micelles to solubilize hydrophobic drugs has problems in that some of the surfactants are relatively toxic and precipitation of hydrophobic drugs occurs when subjected to dilution.
Previously, phospholipid-based liposome formulations for paclitaxel, Taxotere, and other active taxanes have been developed (Straubinger et al. 1993, J. Natl. Cancer Inst. Monogr. (15):69-78; Straubinger et al. 1994; Sharma et al. 1993, Cancer Res. 53(24):557-81; Sharma and Straubinger 1994, Pharm. Res. 11(6):889-96; A. Sharma et al. 1995, J. Pharm. Sci. 84(12):1400-4), and the physical properties of these and other taxane formulations have been studied (Sharma and Straubinger 1994, Pharm. Res. 11(6):889-96; U. S. Sharma et al. 1995, J. Pharm. Sci. 84(10):1223-30; Balasubramanian and Straubinger 1994, Biochemistry 33(30):8941-7; Balasubramanian et al. 1994, J. Pharm. Sci. 83(10):1470-6). The main utility of these formulations is the elimination of toxicity related to the Cremophor EL excipient, and a reduction in the toxicity of the taxane itself, as demonstrated in several animal tumor models (Sharma et al. 1993, Cancer Res. 53(24):557-81; A. Sharma et al. 1995, J. Pharm. Sci. 84(12):1400-4; Sharma et al. 1996, Cancer Lett. 107(2):265-272). This observation holds for several taxanes in addition to paclitaxel (A. Sharma et al. 1995, J. Pharm. Sci. 84(12):1400-4). In some cases, the antitumor potency of the drug appears to be slightly greater for the liposome-based formulations (Sharma et al. 1993, Cancer Res. 53(24):557-81).
These liposomal formulations comprise phospholipids and other additives, in addition to the taxane, and may be stored in a dried state. Upon addition of an aqueous phase to the mixture, particles form spontaneously and may take the form of liposomes (Straubinger et al. 1993). Liposomes are closed, vesicular structures consisting of a limiting bilayer membrane surrounding an aqueous core. A preferred formulation composition (Sharma and Straubinger 1994) contains a neutral (zwitterionic) phospholipid such as lecithin (phosphatidylcholine, 80-90% by mole ratio), along with a negatively charged phospholipid such as phosphatidylglycerol (10-20%). The latter prevents aggregation of the particles through electrostatic repulsion. The most stable taxane content is in the range of 3-4 mole % (relative to total phospholipid content); such liposomes may be physically and/or chemically stable for 2 months after hydration. Under most conditions, paclitaxel formulations containing higher (e.g. 8 mole %) drug concentrations are very unstable and may precipitate within minutes of preparation (Sharma and Straubinger 1994).
The greatest concern over these formulations has been the relatively low taxane content of acceptably stable formulations (3-5 mole %), which necessitates the administration of a large amount of phospholipid (5-10 gm) to patients in order to give the anticipated dose of drug. Although humans frequently are given large amounts of lipids intravenously for Total Parenteral Nutrition (TPN), a major developmental aim has been to produce taxane liposomes having a higher taxane content.
Other approaches to formulating poorly soluble drug for oral or parenteral delivery include, for example, formulations in which the poorly soluble drug is an oil-in-water emulsion, a microemulsion, or a solution of micelles or other multi-lamellar carrier particles. While such approaches may be appropriate for some ionizable as well as non-ionizable hydrophobic therapeutic agents, they fail to take advantage of the unique acid-base chemical properties, and associated solubility properties, of ionizable compounds.
Drugs that are insoluble in water can have significant benefits when formulated as a stable suspension of sub-micron particles. Accurate control of particle size is essential for safe and efficacious use of these formulations. Particles must be less than seven microns in diameter to safely pass through capillaries without causing emboli (Allen et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978; Yokel et al., 1981, Toxicol. Lett. 9(2):165-70).
Another approach is disclosed in U.S. Pat. No. 5,118,528 which discloses a process for preparing nanoparticles. The process includes the steps of: (1) preparing a liquid phase of a substance in a solvent or a mixture of solvents to which may be added one or more surfactants, (2) preparing a second liquid phase of a non-solvent or a mixture of non-solvents, the non-solvent being miscible with the solvent or mixture of solvents for the substance, (3) adding together the solutions of (1) and (2) with stirring and (4) removing of unwanted solvents to produce a colloidal suspension of nanoparticles. The '528 patent discloses that it produces particles of the substance smaller than 500 nm without the supply of energy. In particular the '528 patent states that it is undesirable to use high energy equipment such as sonicators and homogenizers.
U.S. Pat. No. 4,826,689 discloses a method for making uniformly sized particles from water-insoluble drugs or other organic compounds. First, a suitable solid organic compound is dissolved in an organic solvent, and the solution can be diluted with a non-solvent. Then, an aqueous precipitating liquid is infused, precipitating non-aggregated particles with substantially uniform mean diameter. The particles are then separated from the organic solvent. Depending on the organic compound and the desired particle size, the parameters of temperature, ratio of non-solvent to organic solvent, infusion rate, stir rate, and volume can be varied according to the patent. The '689 patent discloses that this process forms a drug in a metastable state which is thermodynamically unstable and which eventually converts to a more stable crystalline state. The '689 patent discloses trapping the drug in a metastable state in which the free energy lies between that of the starting drug solution and the stable crystalline form. The '689 patent discloses utilizing crystallization inhibitors (e.g., polyvinylpyrrolidinone) and surface-active agents (e.g., poly(oxyethylene-co-oxypropylene)) to render the precipitate stable enough to be isolated by, centrifugation, membrane filtration or reverse osmosis.
Another approach to providing insoluble drugs for parenteral delivery is disclosed in U.S. Pat. No. 5,145,684. The '684 patent discloses the wet milling of an insoluble drug in the presence of a surface modifier to provide a drug particle having an average effective particle size of less than 400 nm. The '684 patent discloses the surface modifier is adsorbed on the surface of the drug particle in an amount sufficient to prevent agglomeration into larger particles. Nanoparticles of insoluble drugs prepared under conditions of high shear forces (e.g., sonication, high pressure homogenization, or the like) with biocompatible polymers (e.g., albumin) are disclosed in, for example, U.S. Pat. Nos. 5,916,596, 6,506,405, and 6,537,579 and also in U.S. Patent Publication 2005/0004002 A1.
In view of the foregoing, there is a need for pharmaceutical compositions comprising poorly water soluble drugs with increased physical and chemical stability, which eliminate the use of physiologically harmful solvents and excipients, and methods of production thereof. It is desirable that such pharmaceutical compositions should not degrade, should remain stable under storage conditions and remain physically and/or chemically stable after rehydration. It would also be desirable to have a pharmaceutical composition comprising an anhydrous form of poorly water soluble drug that has greater solubility in traditionally used solvents and excipients, as well as in solvents and excipients that are not physiologically harmful. The present invention provides such pharmaceutical compositions and methods.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entireties.